Abstract
Gout is an inflammatory arthritis caused by deposition of intra-articular monosodium urate (MSU) crystal. Previous studies have focused on resident macrophage, infiltrating monocyte, and neutrophil responses to MSU crystal; yet the mechanisms of cellular changes and the potential involvement of other regulatory immune cells remain largely unknown. Invariant natural killer T (iNKT) cells, an innate type of T cell, are involved in the development of various inflammatory diseases. Here, we investigate the role of iNKT cells in MSU crystal-induced gouty inflammation. MSU crystal-induced inflammatory profiles in an air-pouch model were examined in iNKT-deficient CD1d knockout (KO) and wild-type (WT) control mice. To explore potential mechanisms of iNKT cell regulation of gouty inflammation, we cocultured CD4+ or CD4− iNKT cells with bone marrow-derived macrophages (BMDMs). We found that iNKT cells quickly migrated to the site of inflammation upon MSU crystal stimulation in WT mice. The total number of infiltrating cells in CD1d KO mice, especially neutrophils, was dramatically increased at 6 and 12 h (P < 0.01) post-MSU crystal challenge, compared with WT controls. BMDMs cocultured with CD4+ iNKT cells produced less tumor necrosis factor-α and expressed higher levels of M2 macrophage markers, including Clec7a, Pdcd1Ig2, and interleukin-4 (P < 0.01), compared with BMDMs cocultured with CD4− iNKT cells or conventional CD4+ T cells. CD4+ iNKT cells are one of the key regulators of MSU crystal-induced gouty inflammation through the control of macrophage polarization. iNKT cells may serve as a new therapeutic target for gout.
Highlights
Gout is a paradigm of acute, self-limited inflammation caused by the deposition of intra-articular monosodium urate (MSU) crystal [1]
Monocytes stimulated by MSU crystal can polarize into hyper-inflammatory M1 macrophages, which initiate inflammation via fully functional phagocytizing MSU crystal and delivering to cytoplasmic NACHT-LRR-PYD-containing protein-3 (NALP3) inflammasome, thereby producing tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), both are known as highly inflammatory cytokines, and promoting secondary neutrophil physiologic flow into the site of inflammation [6, 7]
To determine whether Invariant natural killer T (iNKT) cell recruitment is a general feature in MSU crystal-induced gouty inflammation, cellular components in the washing fluid of the air-pouch cavity were analyzed by flow cytometry at different time points post-MSU crystal challenge
Summary
Gout is a paradigm of acute, self-limited inflammation caused by the deposition of intra-articular monosodium urate (MSU) crystal [1]. During the progression of the inflammatory response, MSU crystal provides both of extracellular and intracellular danger signals [2], whose recognition by toll-like receptor 2 (TLR2) and TLR4, as well as CD14, expressed on the surface of monocytes/. INKT Cells in Gouty Inflammation macrophages would initiate MSU crystal uptake [3,4,5]. In contrast to M1 macrophages, anti-inflammatory M2 macrophages can dampen acute MSU crystal-induced inflammation and suppress caspase-1 activation and IL-1β production [8]. The polarization from M1 into M2 macrophages in the development of gout may contribute to self-recovery. It is still unclear how this process is being regulated
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